In Japan, the aging of population is now progressing at the highest speed that has never been experienced, and along with this, the number of patients with dementia is increasing. According to a survey conducted by the National Institute of Population and Social Security Research, the number of patients with dementia is estimated to reach 1.65 million by 2000 and 2.64 million by 2015. Since cares for such patients with dementia become much economic burden, there have been demands for development of an effective treatment method as soon as possible.
A major disease of senile dementias is Alzheimer's disease (Aβ). Although the overview of the pathology of this disease is still unknown, studies are rapidly advancing. Features commonly found in patients with Alzheimer's disease are: (1) atrophy of the brain; (2) deposition of plaque-like substances called senile plaques; and (3) neurofibrillary tangle in which fibrillary substances are deposited inside the neurons. When these three features are found, the patient is diagnosed as Alzheimer's disease. A clinical symptom of Alzheimer's disease, i.e., dementia, is closely associated with neuronal loss. As to the reason why the neuronal loss occurs, the above-mentioned pathological changes provide important clues. According to the advancement of studies since the latter half of 1990s, it has been clarified that senile plaques are deposition of aggregated peptides called amyloid β-protein (Aβ). On the other hand, it has been clarified that the neurofibrillary tangle occurs because tau protein, which is one of the scaffold proteins of the neuron, is phosphorylated and aggregated inside the neuron.
Alzheimer's disease is known to occur in two forms, that is, familial Alzheimer's disease caused by genetic factors, and sporadic Alzheimer's disease that is free from genetic reasons. Causative genes or risk factors of familial Alzheimer's disease are becoming clarified. One of the causative genes of familial Alzheimer's disease is a gene encoding Amyloid Precursor Protein (APP). It is known that when this gene contains a mutant, Alzheimer's disease is caused without exception. Therefore, it is thought that if the effect and function of this mutant can be found, the onset mechanism of Alzheimer's disease would be clarified. Since it is expected that familial Alzheimer's disease and sporadic Alzheimer's disease have a common mechanism, it is thought that some of the researches on the onset mechanism of familial Alzheimer's disease may be applied to the cases of sporadic Alzheimer's disease.
Aβ is cleaved from an APP with β- and γ-secretases. It has been reported that Aβ is classified into Aβ40 and Aβ42 depending on the difference in the cleavage points in which Aβ42 is more likely to aggregate than Aβ40 and that from the pathological observation, Aβ42 firstly aggregates and Aβ40 then aggregates around Aβ42 as a core to form fibrils. Recent studies by the present inventors provide findings that Aβ starts to be deposited in the Aβ brain via binding to GM1 ganglioside (hereinafter, abbreviated as “GM1”) (K. Yanagisawa, A. Odaka, N. Suzuki, Y. Ihara, Nat. Med. 1, 1062 (1995); K. Yanagisawa, Y. Ihara, Neurobiol. Aging 19, S65 (1998)). Furthermore, the present inventors reported that a monoclonal antibody (antibody 4396) that specifically recognizes GM1-bound Aβ was successfully produced (FEBS Letters 420, 43-46 (1997)). Based on the unique molecular characteristics of this GM1-bound Aβ, the present inventors hypothesized that Aβ adopted an altered conformation via binding to GM1 and functioned as a seed of the formation of amyloid fibrils (K. Yanagisawa, A. Odaka, N. Suzuki, Y Ihara, Nat. Med. 1, 1062 (1995)). Subsequently, several investigators performed in vitro studies and their findings support the above-mentioned hypothesis; i.e., Aβ specifically binds to GM1 on the membranes; soluble Aβ starts to aggregate and form amyloid fibrils following the addition of GM1-containing liposomes (J. McLaurin, A. Chakrabartty, J. Biol. Chem. 271, 26482 (1996); P. Choo-Smith, W. K. Surewicz, FEBS Lett. 402, 95 (1997); P. Choo-Smith, W. Garzon-Rodriguez, C. G. Globe, W. K. Sutrewicz, J. Biol. Chem. 272, 22987 (1997); K. Matsuzaki, C. Horikiri, Biochemistry 38, 4137 (1999); V. Koppaka, P. H. Axelsen, Biochemistry 39, 10011 (2000)).
Thereafter, in regard to the molecular mechanism in which GM1-bound Aβ is formed, it has been reported that binding of Aβ to GM1 is dependent on the concentration of cholesterol in the membranes to be bound; i.e., a high concentration of cholesterol enhances the binding of Aβ to GM1 via facilitating the formation of GM1 “cluster” in the membranes (A. Kakio, S. Nishimoto, K. Yanagisawa, Y Kozutumi, K. Matsuzaki, J. Biol. Chem., 276, 24985 (2001)). Furthermore, Aβ may bind to GM1 on synaptic membranes of the aging brain since the cholesterol concentration in the exofacial leaflets of synaptic membranes significantly increases with age and/or with the deficiency in apolipoprotein E (Apo E) (U. Igbavboa, N. A. Avdulov, F. Schroeder, W. G. Wood, J. Neurochem. 66, 1717 (1996); U. Igbavboa, N. A. Avdulov, S. V. Chochina, W. G. Wood, J. Neurochem. 69, 1661 (1997)). While, Aβ may bind to GM1 in GM1-rich and cholesterol-rich membrane domains (referred to as rafts) since the rafts physiologically contain a large amount of Aβ and in the rafts, insoluble Aβ are deposited in a kind of mouse model with familial Alzheimer's disease (R. G Parton, J. Histochem. Cytochem. 42, 155 (1994); K. Simons, E. Ikonen, Nature 387, 569 (1997); S. J. Lee et al., Nat. Med. 4, 730 (1998); M. Morishima-Kawashima, Y. Ihara, Biochemistry 37, 15274 (1998); N. Sawamura et al., J. Biol. Chem. 275, 27901 (2000)).
Thereafter, the present inventors have shown that a seed of the Aβ fibril formation (GAβ complex) in the living body included GM1 by an immunological procedure using an antibody (4396C) and that this antibody recognized a GAβ complex from the Alzheimer's disease brain and suppresses the Aβ polymerization using GAβ complex as a seed. From these results, the present inventors have suggested that, as a core of the amyloid hypothesis describing the onset mechanism of Alzheimer's disease onset, a mechanism of formation of a seed of Aβ fibril formation actually occurs in the living body (WO 03/014162, J. Neurosci., 2004, 24: 4894-4902).
[Patent Document 1] WO 03/014162
[Non Patent Document 1] K. Yanagisawa, A. Odaka, N. Suzuki, Y. Ihara, Nat, Med. 1, 1062 (1995)
[Non Patent Document 2] K. Yanagisawa, Y. Ihara, Neurobiol. Aging 19, S65 (1998)
[Non Patent Document 3] FEBS Letters 420, 43-46 (1997)
[Non Patent Document 4] J. McLaurin, A. Chakrabartty, J. Biol. Chem. 271, 26482 (1996)
[Non Patent Document 5] P. Choo-Smith, W. K. Surewicz, FEBS Lett. 402, 95 (1997)
[Non Patent Document 6] McLaurin J, Chakrabartty A, Eur J. Biochem. 245(2)355 (1997)
[Non Patent Document 7] P. Choo-Smith, W. Garzon-Rodriguez, C. G. Globe, W. K. Sutrewicz, J. Biol. Chem. 272, 22987 (1997)
[Non Patent Document 8] K. Matsuzaki, C. Horikiri, Biochemistry 38, 4137 (1999)
[Non Patent Document 9] V. Koppaka, P. H. Axelsen, Biochemistry 39, 10011 (2000)
[Non Patent Document 10] A. Kakio, S. Nishimoto, K. Yanagisawa, Y. Kozutumi, K. Matsuzaki, J. Biol. Chem., 276, 24985 (2001)
[Non Patent Document 11] U. Igbavboa, N. A. Avdulov, F. Schroeder, W. O. Wood, J. Neurochem. 66, 1717 (1996)
[Non Patent Document 12] U. Igbavboa, N. A. Avdulov, S. V. Chochina, W. G Wood, J. Neurochem. 69, 1661 (1997)
[Non Patent Document 13] R. G Parton, J. Histochem. Cytochem. 42, 155 (1994)
[Non Patent Document 14] K. Simons, E. Ikonen, Nature 387, 569 (1997)
[Non Patent Document 15] S. J. Lee et al., Nat. Med. 4, 730 (1998)
[Non Patent Document 16] M. Morishima-Kawashima, Y. Ihara, Biochemistry 37, 15274 (1998)
[Non Patent Document 17] N. Sawamura et al., J. Biol. Chem. 275, 27901 (2000)
[Non Patent Document 18] J. Neurosci., 2004, 24: 4894-4902